Alzheimer's disease (AD) is globally the most common cause of dementia with a significant societal and economic impact. Currently available therapies have a minimal effect of cognitive decline and do not address the underlying disease pathogenesis. Immunomodulation has shown great promise as an AD therapy, even though the initial clinical trial was associated with severe adverse effects in a minority of patients. Our research group postulated stimulation of the innate immune system as possible alternative method for modulating amyloid and tau related pathologies, without associated toxicity. In our initial studies we utilized type B CpG ODN to stimulate the innate immune system via Toll-like receptor 9 (TLR9) in the Tg2576 AD mouse model and showed this to be highly effective at reducing the parenchymal and vascular amyloid burden, along with A oligomers, correlating with behavioral improvements. Moreover, our recent findings in the triple-transgenic (3xTg) AD mice document that stimulation of TLR9 signaling has the advantage of concurrently addressing both A and tau pathologies. A significant concern with immunotherapy is clearance of vascular amyloid and associated microhemorrhages. This is an important issue, since cerebral amyloid angiopathy (CAA) is a common feature of patients with AD and cognitively normal elderly individuals. CAA is an age-related disorder of the brain vasculature that causes 20% of non-traumatic cerebral hemorrhage in humans. Solving the problem of CAA is becoming a priority for ensuring the success of immunotherapy. Our preliminary studies showed that CpG ODN treatment reduced CAA pathology without any evidence of increased cerebral microhemorrhages. To further assess any future potential human use of CpG ODN we plan to test this approach in a more biologically proximate and well established non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis) and to begin treatment at a point where CAA is already present. Immunologic and vascular similarities of squirrel monkeys to humans support the use of this model for testing emerging therapies for AD related pathology, and CAA in particular. One consideration in designing therapeutic vaccines is immunosenescence in old animals. For this reason our initial short term duration studies will be performed in young monkeys. For our long term studies in adult animals we will select a dosage with the greatest efficacy and safety profile. Overall, we believe that the proposed studies are essential to further optimize this novel immunotherapeutic approach to make use of CpG ODN more feasible for human application.